JPS59501458A - Novel substituted derivatives of 2,5↓-diamino↓-1,4↓-diazole, their preparation and pharmacological compositions containing the derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] 2.5-Di-γmino-1,4-)γ-nol novel substituted derivatives, their production process and Pharmaceutical compositions containing derivatives The present invention relates to novel nitrogen-containing heterocyclic derivatives, methods for producing the same, and The present invention relates to pharmacological compositions containing these.

The present invention particularly relates to 2,5-/amino-1,4-n γ-so- Use the text for a purpose.

Specifically, the present invention relates to 2-Ryo Mitsuno r-1,4-diazole of the following general formula <1) It is intended for the purpose of or represents a peteroaryl group, and X consists of -(CL)n-1CII OII an optionally substituted alkylene group selected from the group, where n is 1.2.3 or or 4, nl is 1.2 or 3, n' is Oll or 2, and N et is a general formula (△).

, - Trowel R: +i is hydrogen, lower alkyl group, aryl group or (lower aralkyl group) Group 4, and general formula (I() , ding; Th　F　7 is 1-11. J(, N　R3 or oxygen (however, R1 is a lower alkyl group, aryl group or lower aralkyl group) in Table 1, represents a group selected from the group consisting of

Similarly, the present invention provides the compound of the general formula (1) with an acid or a compound represented by the general formula (1). ; with L acid , preferably pharmaceuticals” - also relates to permissible addition salts.

The present invention relates to 4) optical isomers of the compound of general formula (1). The molecule is Contains at least one asymmetric carbon and therefore has dextrorotatory or levorotatory isomers Can be separated.

If that'-1X or fast chain-[Cll0I+-(CL)) n,-, then new Another asymmetric center appears, making it possible to separate the noastereo-7-isomers. , it becomes possible to divide the optical isomers of the compound into two.

Finally, if Ar is a partially saturated vinclo group, one complementary asymmetric carbon exists, offering new possibilities for separation. As a result, in this case the molecule is It is possible to write as below: In this structural formula, Y and Y' are mutually independently -C11゜-1-〇-1-8- Or represents a -Nl+- group.

When substituent Z is oxygen, the heterocyclic structure is 2,5-noamino-3-oxt-1, , 4-noasole structure.

When the substituent Z is an imino group, i.e. 111, the heterocyclic structure is 2,5-noa The structure of the sole of Minnow 1, 3, 4-1 is different. This includes two types of inputs: : / 1. IJ asole tautomer existence 1 ~ obtained Among the various examples of the radical Ar, the following may be mentioned in particular: a) pyranone, oxano pyranone, and the general formula, where R is hydrogen, lower alkyl, lower alkoxy, Halogen, trifluoromethyl, sulfonamide, trifluoromethoxy, silicon Ann, carboxy, carbalkoxy, carboxamide, nitro, alkylene di is an oxy group, and p is an integer in the range of 1 to 3, such as a phenyl group represented by Monocyclic aromatic group; b) tetrahydronaphthyl, (1 or 2)-naphthyl, pen Tudioxanil, pentudioxanil, kirynyl, thiachromanil or (2 or 3) -saturated or partially saturated bicycloaromatics such as indolyl groups. Base.

Preferably, the group Ar is a substituted or unsubstituted phenyl, pyridyl group, tetrahydrona Phthyl or benzodioxanyl.

Substituent X is a linear or branched alkylene chain having 1 to 4 carbon atoms, carbon a human'roxyalkylene chain having 2.3 or 4 atoms or 2.3 or 4 carbon atoms; is a ketalized oxoalkylene chain of 4.

The nature and length of the alkylene chain as a function of n5n1 and n' play an important role. and condition the intensity or duration of the pharmacological action of the compound of general formula (I). It is something that

The compounds of general formula N) are divided into the following five subgroups which are particularly preferred in practice: I get kicked.

a) Racemic or optically active (phenylalkyl) of the following general formula (IA) -piperidine: n" is as defined above, Z is NH1NR3 (R3 is as defined above ) or represents oxygen.

b) Racemic or optically active (phenylalkyl) represented by general formula (IB) )-Piperidine: where the substituents R, Rs, K', p, nl and n.

is as defined above.

C) Racemic or optically active (benzo-1, 4-dioxanyl)-alkyl-piperidine: However, R, K', Z, p, n' and nl are as defined above.

d) Racemic or optically active (benzo-1,4 -dioxanyl) ~alkyl group-°methin: Here, substituents R, K', R3, nl, n' and p are as defined above. Ru.

e) Indolyl-(2 or 3)-alkyl-piperi represented by general formula (IE) gin: Here, the substituents R, K', Z and p, n, , n' are as defined above.

As far as the present invention is concerned, lower alkyl groups are, for example, methylethyl, isopropyl, 5ec-butyl, tert-butyl, pentyl, neopentyl and n-hexy A linear or branched hydrocarbon group having 1 to 6 carbon atoms.

A lower alkoxy group is a straight or branched alkyl chain having 1 to 1 carbon atoms. 6, such as methoxy, ethoxy, isopropoxy, tert-butoxy or n-pentyloxy group.

The term "halogen" represents a chlorine, bromine, iodine or fluorine atom. preferable The substituent is fluorine.

The term "aryl" refers to lower alkyl, halogen, lower alkoxy, as the case may be, , 1 selected from the group consisting of alkylenedioxy and trifluoromethyl groups, Monocyclo, homocyclo or heteroaromatic substituted with 2 or 3 substituents shall mean an aromatic group.

The term "aralkyl group j is a straight or branched alkyl chain having 1 to 6 carbon atoms. It represents a substituted aromatic group as described above.

Among the addition salts of the compound of general formula (1), especially hydrochloride, hydrobromide, sulfate, nitrate acid salts, phosphates, thiosulfates, formates, acetates, maleates, fumarates, ( methquine salicylate), 3,4.5=trimethinebenzate, vanilet 〇-Carpoethoxysyringoate, Naphtonite, Pencenesulfonate , methanesulfonate, isothionate, nicotino-1-, isonicotinate, Examples include embonate and glucose-phosphate.

Acids which cannot be used therapeutically, such as iodate, for purification or isolation Useful.

The compounds according to the invention exhibit their pharmacologically interesting properties, especially on the central nervous system. It is characterized by antihypertensive properties with low analgesic effect. High levels of these compounds Due to its activity, general formula (1) or its addition salts eliminate the effects of hypertension, used in human or animal treatment, as a main component of medicines to reduce or I know what I can do.

Ultimately, these compounds can be administered parenterally, orally, rectally or sublingually as pharmacological compositions. used to.

The pharmaceutical composition contains at least one compound of general formula (1) or Addition salts of inorganic or organic acids may be combined with pharmaceutically acceptable inert auxiliaries or vehicles. Contained as a combination or mixture.

Preferred forms of administration include bare or coated tablets, capsules, gels, dragees. tablets, multilayer tablets, intravenous drops, drinkable solutions or (J suspensions, multi-dose bottles BL< Solutes or suspensions for injection divided into ampoules, skewers, etc. Examples include sublingual tablets.

The pharmaceutical composition according to the present invention further comprises 1. have the same effect, auxiliary effect or synergistic effect - At least one other component may be included. Thus, the thiasisin type or triaminopteridine-type diuretics, or propranolol, pindo A β-blocking agent such as roll or atenolol can be added.

- The daily dosage is based on therapeutic instructions, route of administration, patient age and patient history of hypertension. can be varied within a wide range. The general standard is that the dosage for adults is Dispense 01-50mg per dose and range from 01-150mg per day It is within.

Preferably, the pharmaceutical composition of the present invention contains the main component of general formula (1) or a salt thereof as a unit. Contain within the range of 0.1 to 25 mg per administration finger.

The present invention also relates to a process for producing compounds of general formula (I), characterized in that the compounds of general formula (n ) of N~cyano-isothiourea or isourea: Here, Ar, X and n'' are as defined above, and Z'' is oxygen or sulfur source. and R4 is a lower alkyl group, is the general formula (■).

NZ-NH2(ITI> Here Z is as defined above, When Z is an oxygen atom, the general formula (I ’) d and when 2 is an imino group -N11-, the general formula (■'').

-(forms the 2-j'mino-1,,3,4-triazole shown, and Z is a group -NRJ, it is represented by the following formula and can be separated by physical means, Based on forming a mixture of converted 2-amino-1,3,4-)gammasols. 2□ - (001.2.L, kU-R, are as defined above)], Generated by inorganic or organic acids or by functional group exchange with carboxylic acids. Hydrolyze the ketal to obtain a carbonylated compound represented by general formula (1) I can do it.

The carbonylated compound of general formula (■) is a mixed alkali metal hydride, such as a Reacting alkali metal porohydrates or alkali metal aluminohydrates. 17': Aluminum isofuro under Meerwein reaction conditions. Exchange reaction with secondary alcohol in the presence of pyrate or lower alkano General formula (V): Hydroxylation inducer by forming hydroxyalkylated compound shown as Can be reduced to a conductor.

The carbonylated compound is also subjected to 1lolff-Kishner reaction conditions. hydrazine under the conditions or Clem-mensen reaction conditions. alkyl by treatment with a solution of zinc in hydrochloric acid to obtain the alkylated compound can be reduced to chemical derivatives.

The resolution of compounds of general formula (I) can be carried out using optically active acids such as d-tartaric acid, d-di Benzoyltartaric acid, d-diethyltartramic acid, pimaric acid, abietic acid, d-camphosulfonic acid, optically active naphthalenedioxyphosphonic acid or curco This can be carried out by forming a salt with ester-6 or 1-phosphonic acid.

The starting material cyanoisourea or isothiourea corresponding to general formula (II) is It can be prepared according to the following method. That is, the method is calculated using the general formula (■): , X and n' are as defined above, General formula (■): However, R4 and R9 are lower alkyl groups. cyanoiminoisodithiocarbonate and general formula (■): However, R4 and R5 are as defined above. Reaction with a cyanoimination reagent selected from the group consisting of iminoisothiocarbonates Let, the general formula (■): Here, A", R4 and n' are as defined above, and Z" is an oxygen or sulfur atom. is, It consists of forming isothiourea or isourea shown in

The present invention will be explained below with reference to Examples, but these should not be construed as limiting the present invention. isn't it.

JJjlJl 1-(1,4-benzodioxan-2-yl-methyl)-4-( 2-Amino-3-)lyazol-5-yl-aminomethyl)-piperidine 1-(1,4-benzodioxan-2-yl-methyl)-4-(N-cyano-8 -Methylisothioureidomethyl)-piperidine 7.2 g, hydrated hydrazine 4. A mixture of 5 mβ and 100 mj2 of ethanol is boiled for 4 hours.

This solution was then concentrated to dryness to obtain a paste, which was treated with acetonitrile. Colorless crystals are obtained which are separated by filtration, washed and dried.

5 g of the claimed product were thus obtained. When this was reconstituted with ethyl acetate The melting point was 157-8°.

-methyl)-4-(2-amino-3-)lyazol-5-yl-amino)-pipe Lysine 1-(1,4-benzodioxan-2-yl-methyl)-4-(N-no Anor 8-methyl-isothioureido)-piperidine 4g, hydrous hydrazine 4m 1 and 100 mff of ethanol are boiled for 4 hours.

0 Concentrate this to dryness and redissolve the resulting paste in acetonitrile to form white crystals. 3.2g was obtained.

It was purified by recrystallization in isopropanol.

Thus, m, p, -2] 1-(1,4-benzodioxa (2-yl-methyl)-4-(2-amino-8-triazol-5-yl-a mino)-piperidine was obtained.

methyl)-4-(2-amino-L 3.5-oxadiazol-4-yl-ami -Piperidine 1-(1,4-benzodioxan-2-yl-methyl)-4-1N-cyano-8 -Methyl-isothioureido)-piperid 77 g, hydroxylamine hydrochloride 4. 2g of bicarbonate) A mixture of 5.2g of IJum and 20ml of ethanol for 4 hours. Boil.

The solution was then concentrated to dryness and the translucent solid was isolated and redissolved in acetonitrile. Understand.

It first dissolves and then crystallizes.

The crystals are filtered, washed with acetonyl-IJ and dried.

Double melting point, i.e. first melts at 141-2°, then solidifies and 167-8° 2.9 g of a claimable product was obtained which melted at .

Example 4 1-(C4-benzodioxan-2-yl-ethyl)-4-(2-a Mino-8-triazol-5-yl-aminomethyl)-piperidine 1-<1.4 -benzodioxan-2-yl-ethyl)-4-(N-anor S~methyliso 75 g of thiouridomethyl)-piperidine, 4.5 mff of hydrated hydrazine and A mixture of 100 mβ ethanol is boiled for 4 hours.

After concentration to dryness, a paste is obtained, which can be ground in acetonitrile. crystallizes.

The crystals are filtered, washed with acetonitrile and dried.

Purification by recrystallization in isopropanol gave 5 g of the desired product, melting point 148°.

sadian-4-yl-aminomethyl)-piperidine 1,-(1,4-benzodioxan-2-yl-ethyl)-4-(N-cyano- 7.5 g of 8-methylisothioureidomethyl)-piperidine, hydroxylamine Mixture of 2.1 g of hydrochloride, 5.1 g of sodium bicarbonate and 100 mA of ethanol The material was boiled for 20 hours.

After filtration, it was concentrated to dryness to obtain a semi-solid oil, which was poured into a 50 m# hot isopropyl solution. Dissolved in the bottle.

After cooling for a while, crystallization occurred, and the crystals were filtered off and dried.

Purified by recrystallization with ethanol as crystals containing 1/2 mole of water of crystallization. 2.6g of the target compound was obtained. It exhibited two melting points. That is, first melt at 75°. It melted, then solidified, and melted again at 1.28°.

Starting material, '], -(]1.,4-benzodioxan-2yl-ethyl) -4-(N-cyano-8-methylisothioureidomethyl)-piperidine is as follows: obtained in a similar way.

1-(L4-benzodioxan-2-yl-ethyl)-4-aminomethylpiperi 73 g of gin, 33.6 g of N-cyanoimino-dimethyl-dithiocarbonate and A mixture of 500 m6 of water and ethanol is boiled for 4 hours.

The product, which crystallizes on cooling, is filtered, washed with ethanol and dried.

Thus, the two molecules first melt at 145°, then solidify, and then melt again at 155°. 85 g of the target compound are obtained as white crystals with a melting point of .

Example 6 1-[(6-methyl-1,4-benzodioxa↓JIAI-[(6- Methyl-1,4-benzodioxane)-2-yl-methyl]-4-(N-cyano -8-methylisothioureidomethyl)-piperidi1-[(6-methyl-1,4 -benzodioxane)-2-ylmethyl]-4-aminomethyl-piperidine 5 8.4 g, 31 g of N-cyanoimino-dimethyl-isodithiocarbonate and A mixture of 400 mβ of ethanol is heated and boiled for 4 hours.

The product, which crystallizes on cooling, is filtered off, washed with ethanol and dried. this is A white crystal with a melting point of 145° is 1,-[(6-methyl-1,4-benzodioxa -2-yl-methyl]-4-(N-cyano-8-methylisothioureido) - 7.5 g of piperidine with 4.5 mA of hydrous piperidine and 100 ml of ethanol Heat to reflux for 4 hours with a mixture of water and alcohol.

After concentration to dryness, the resulting paste was redissolved in acetonitrile and crystallized. .

Thus, 6.5 g of white crystals were obtained. This can be recombined in the isoproper tool. It was possible to purify it by

1, -[(6-methyl-1,4-benzodioxane)-2-yl-methyl] - 4-(2-amino-8-triazol-5-yl-aminomethyl)-piperidine is a substantially colorless crystal with a melting point of 138°.

3,5-Oxadiazol-4-yl-amino-methyl)-piperidine 1 [(6-methyl-1,4-benzodioxane)-2-yl-methyl]-4 -(N-cyano-8-methylisothioureidomethyl)-piperidine 7.5 g, Hydroxylamine hydrochloride 4.2g, sodium bicarbonate io, 2g and ethanol The mixture was heated at 1.00 mA for 4 hours and boiled.

After filtration, the ethanol solution was concentrated to dryness, the dried residue was dissolved in water, and the ethanol solution was concentrated to dryness. It was extracted with form and the organic phase was separated.

After drying and concentrating to dryness, it was reconsolidated in isopropanol to obtain 5.7 g of product. . Melting point 146°.

Example 8 1-(1,4-penzodioxan-2-ylmethyl)-4-(2- Amino-1,3,5-oxacyazol-4-yl-aminomethyl)-piperidi hmm 1-(1,4-penzothioxan-2-yl-)1,4-(N-cyano-8) 7.2 g of -methylisothioureidomethyl)-piperidine, hydroxylamine salt 2.1 g of acid salt.

Boil a mixture of 5.1 g of sodium bicarbonate and ethanol LOOrnl for 4 hours. did.

After filtration, it is concentrated to dryness to obtain a semi-solid amorphous product that cannot be crystallized.

This product was obtained using a 9-1 mixture of chloroform and isopropylamine as the eluent. It is purified by passing it through a H-Merck silica column.

The product obtained after elution and evaporation of the solvent is then purified with a minimum amount of acetonyl Crystallizes by treatment with

3.8 g of the desired product were thus obtained as white crystals with a melting point of 130-131°.

Example 91-[(1,4-pensosioxan-2-yl-(2-hydroxyethyl) L))-4-(2-amino-L 3.5-oxaneazol-4-yl-amino methyl)-piperidine E-loose 1q 1-[(i, 4-benzodioxan-2-yl-(2-hydroxy ethyl)]-4-(N-cyano-8-methylisothioureidomethyl)-piperi gin 1-[:(1,4-benzodioxan-2-yl-(2-hydroxyethyl)] -]4-aminomethyl-piperidine 58gN-cyanoimino-dimethyl-dithi A mixture of 29 g of ocarbonate and 400 mj2 of ethanol was heated for 4 hours, Boil.

This solution was then concentrated to dryness and redissolved in isopropyl ether to obtain crystals, This is filtered off, washed with isopropyl ether and dried.

Reconsolidation in isopropanol gives 58 g of the desired product, melting point 128°. Obtained.

Process B 1-[:1.4-benzodioxan-2-yl-(2-hydroxyethyl)]- 4-(N-cyano-8-methylisothioureidomethyl)-piperidine 7.8g , 2.1 g of hydroxylamine, 5.1 g of sodium bicarbonate and 10 g of ethanol Boil the mixture at 0 mA' for 20 hours.

After filtration, the reaction mixture was concentrated to dryness to obtain a paste-like solid, which was evaporated under heat with isopropylene. Redissolve in Ropatool.

After 24 hours, solid precipitation was observed, which was filtered off and washed with isopropyl ether. , reconsolidate in a small amount of ethanol.

Thus, the objective as a crystal with a melting point of 148-150° with 172 moles of water of crystallization. 1.7 g of product was obtained.

Example 10 1-[1,4-benzodioxan-2-yl-(2-hydroxyethyl) ]-4-(2-A 1-'[1,4-benzodioxylene obtained in Step A of Example 8 San-2-yl-(2-hydroxyethyl)]-4-(N-cyano-8-methy 7.8 g of lysothioureidomethyl)-piperidine, 5 mff of hydrated hydrazine, and and 100 ml of ethanol are boiled for 4 hours.

After concentration to dryness, a paste was obtained, which was treated with acetonyl-IJ. Let it solidify.

The product was filtered off, washed with isopropyl ether, dried and dissolved in isopropyl ether. Reconnect.

2 g of the desired product were thus obtained as crystals with a melting point of 164°.

Example 11 1-(1,4-benzodioxan-2-yl-methyl)-4-(2 -amino-3-methyl-3-)lyazol-5-yl-aminomethyl)-piperi dine and 1-(1,4-benzodioxan-2-yl-methyl)-4-(2- Amino-4-methyl-3-)lyazol-5-yl-aminomethyl)-piperidi gin 1-(1,4-benzodioxan-2-yl-methyl)-41N-cyano-8- 3.6 g of methylisothioureidomethyl)-piperidine, 8 m of methylhydrazine A mixture of j2 and 50 mA of ethanol is boiled for 18 hours.

After concentration to dryness, an oil was obtained, which was composed of chloroform-isopropylamine 9:1 In-system thin layer chromatography shows two spots.

These two products were eluted with a 9:1 mixture of chloroform-isopropylamine. It is separated by passing through an H-Merck silica column used as a silica column.

Thus, 1.4 g of an initially eluted oil was obtained, which was composed of isopropyl ether. Crystallizes by treatment with ether.

This product corresponded to the 3-methyl derivative and had a melting point of 129-130°.

Elution continued and 0.7 g of oil was separated, which was treated with isopropyl ether. It crystallizes by treatment and corresponds to a 4-methyl derivative. This product has a melting point of 1 It was 39-140°.

When phenylhydrazine is used instead of methylhydrazine, 3-phenylhydrazine is also used. A mixture of phenyl and 4-phenyl derivatives is obtained, which are cured on silica. Separated by romatography.

The use of isopropyl hydrazine similarly produces 3-isopropyl derivatives and A mixture with 4-isopropyl derivatives is obtained, which is chromatographed on a silica column. Separated by matography.

Example 12 1-[(4-phenyl-4-oxo)-1-butyl L-4-(2-a Mino-S-triazol-5-yl-aminomethyl)-piperidine)-1-buty ]-4-(N-cyano-S-methylisothioureidomethyl)-piperidine 1-[:(4-phenyl-4,4-ethylenedioxy)-1-butylcou-4-a Minomethyl-piperidine 82.3 & 1N-cyanoimino-dimethyl-dithiocal A solution of 39.5 g of bonate and 400 mA of ethanol is heated to reflux for 4 hours.

The solution was then concentrated to dryness and the resulting oil was redissolved in isopropyl ether. let

105 g of the desired product were thus obtained as white crystals with a melting point of 136°.

Eve-dan 1-[(4-phenyl-4-amino-ethylenedioxy)-1-butyl]-4- 8 g of [(N-cyano-8-methylisothiourido)-methyl]-piperidine, Hydrous hydrazine 4.5mj! and ethanol Loomβ were heated for 18 hours and boiled. Boil.

After concentration to dryness, a translucent oil was obtained, which was dissolved in ethyl acetate and cooled. Crystallize by cooling.

6.3 g of product with a melting point of 134° were thus obtained.

The acetal was dissolved in 150 mβ of IN hydrochloric acid and kept at ambient temperature for 18 hours. It was hydrolyzed by

Then, P)l is adjusted to 10 with caustic soda solution and crystallized.

After filtration, washing with water, drying and recrystallization in isopropyl alcohol, the melting point was 154. 5.2 g of product were obtained.

Example 1.3], -C(4-phenyl-4-oxo)-1-ureidomethyl)- piperinone 16.1 g, sodium bicarbonate 8.4 g, hydroxylamine hydrochloride 7 ．． A mixture of 2 g and 200 ml of ethanol is heated under reflux for 18 hours.

After filtration, it was concentrated to dryness to obtain a semi-transparent semi-solid product, which was dissolved in ethyl acetate under heating. and crystallize it.

After filtering off the crystals, washing and drying, a white product with a melting point of 126° was obtained.

This ketal is dissolved in 150 mA IN hydrochloric acid and left at ambient temperature for 18 hours. This resulted in hydrolysis.

Reconstitution in basic medium with caustic soda solution yields an oil, which can be ground This results in crystallization.

After filtration, washing with water, drying and reconsolidation in isopropanol, the melting point was 80-82. 5 g of product were obtained.

5-1-Riazol-5-yl-aminomethyl)-piperidine. ]-[(4-p-fluorophenyl-4,4-ethylenedioxy)-1-butyl ]-4-(N-/ano-8-methylisothioureidomethyl)-piperidine 3 A mixture of 3.6 g, 15 mI2 of hydrous hydrazine and 400 mI2 of ethanol was added to 1 Boil for 6 hours.

After concentration to dryness, a viscous oil was obtained, which was then treated with ethyl acetate. More crystallized.

In this way, 27.5 g of crystals with a melting point of 145° were obtained.

This ketal was dissolved in 600 mA of IN hydrochloric acid and allowed to stand at ambient temperature for 18 hours. It is hydrolyzed by

Next, caustic soda was added to prepare a basic medium with pH=10, and the precipitate was washed with water. dry.

In this way, it was re-crystallized in acetonyltrile to obtain 25 g of white crystals. This is 16 It melts at 5°, then solidifies and melts again at 185° (two melting points).

Example 15 1-[(4-p-Fluorophenyl-4-H) Cooled to 10° and heated to 9 /-100m R23.9g of 1-yl)-dimethyl]-piperidine Add 1 g of sodium borohydrate to the dissolved solution while stirring. do.

After stirring for 1 hour and 30 minutes at ambient temperature, crystallization occurred.

It is filtered and washed with water and ethanol.

After reconsolidation in ethanol, 2.1 g of white crystals with a melting point of 21° were obtained.

1,3,5-Oxadiazol-4-yl-aminomethyl)-piperidine 1,-1:(4-p-fluorophenyl-4,4-ethylenedioxy)-1-but ]-4-(N-noano8-methylisothioureidomethyl)-piperidine , 3.6 g of hydroxylamine hydrochloride, 4.2 g of sodium bicarbonate and ethanol ], 00 ml of the mixture is boiled for 17 hours.

After filtration, the produced ketal was concentrated to dryness to obtain a translucent oil, which was diluted with 200% IN hydrochloric acid. m1 and hydrolyze the ketal group.

After standing for 20 hours at ambient temperature, the solution was made basic with caustic soda and chloroform. Extract with system.

The oil obtained after evaporation of the solvent was used as the eluent and Passing through an H-Merck silica column using a 9:1 mixture of pyramines More refined.

Thus, the oily substance 2.2 that crystallizes upon treatment with -r7tonitrile I got g.

1] product was obtained as white crystals with a melting point of 1:)4°.

Example 171-[(4-p-fluorophenyl-4,4-ethylenedioxy)- 1-butyl]-4-(2-amino,-3-methyl-s-triazole-5-y -aminomethyl)-piperidine and 1-[(4-p-fluorophenyl-4 ゜4-ethylenedioxy)-1-butyl]-4-(2-amino-4-methyl-3 -) lyazol-5-yl-aminomethyl)-piperidine 1-[(4-p-ph- fluorophenyl-4,4-ethylenedioxy)-1-butyl E-4-(N-cya) 40 g of no-8-methylisothioureidomethyl)-piperidine, methylhydrazi A mixture of 100 mj2 of water and 300 ml of ethanol is boiled for 18 hours.

After evaporation to dryness, 47 g of oil was obtained, which was dissolved in acetonyl 1-IJ 25 g under heating. Redissolve in 0m6. This solution crystallizes as it stands overnight. Separate the crystals Filter, wash with acetonyl-IJ and dry.

14 g of a colorless product with a melting point of 100° were obtained. This is true for thin layer chromatography. It was uniform (Rf = 0.25>).

The solution was concentrated to dryness and the oily dry residue was subjected to thin layer chromatography with Rf= Two spots of 0.25 and 0.1 are shown.

These two compounds were mixed with a chloroporum-isopropylamine mixed solution as an eluent. Chromatography on H-Merck 1.600 kg silica column using medium Separated by roughy.

Example 18 1-C(4-p-fluorophenyl-4-oaminomethyl)-pipe lysine 12.5 g of 1-[(4-p-fluorophenyl-4,4-ethylenedioxy) -1-butyl]-4-[(2-amino-4-methyl-3-)lyazol-5-y )-Aminomethyliopiperidine was dissolved in 500 mA of IN hydrochloric acid at ambient temperature. Let stand for 11 hours.

The mixture is then rendered alkaline with caustic soda and extracted with ethyl acetate.

After washing the organic phase with water, drying and concentrating, an oil was obtained which was dissolved in acetonitrile. 3.9 g of white crystals were obtained.

1-1: (4-p-fluorophenyl-4-oxo)-1-butyl)-4-[( The melting point of 2-amino-4-methyl-8- was 114-115°.

Example 19 1-[(4-p-fluorophenyl-4-oxo)-1-butyl] -4-[:(2-amino-3-methyl-S-, +-riazol-5-yl)- 3.5 g of 1-[(4- , p-fluorophenyl-4,4-ethylenedioxy)-1-butyl]-4-C Prepare a (2-amino-3-methyl-3-)lyazole solution.

After standing for 18 hours at ambient temperature, the aqueous solution was made alkaline with caustic soda and etched. After extraction with acetate and concentration of the solvent, a solid was obtained9, which was They are reunited in the room.

In this way, 1.3 g of the target compound was obtained as crystals with a melting point of 162°.

Example 20 1-[(4-p-fluorophenyl-4-oxo)-1-butyl] -4-[(2-amino-4-methyl-1,3,4-)riazolyl-5-amino) -methyl]-piperidine Process A Benzaldehyde 10.65g, methylhydrazine 4.6g and ethanol 100rr+j2 was heated to reflux for 30 minutes. After concentration to dryness, it is vented as a transparent oil. N-methylhydrazine of zaldehyde is obtained. This is 100mj! of ethanol and added 14.6 g of methyl N-cyano-iminodithiocarbonate. I can do it. This was refluxed for 2 hours, the solvent was evaporated to dryness, the oily residue was collected and the isopropylene Crystallize by trituration in ether.

After filtration, the crystals are washed and dried as colorless crystals with a melting point of 114° (cyanoimimum -(Methylthio)-methyl-N-methyl-N-benzylizonylhydrazine I got it.

Process B 3.25 g of hydrazine in step A, 1-[(4-p-fluorophenyl-4,4 -ethylenedioxy>1-butyl]-4-aminomethyl-piperidine 4.5g and 50m of ethanol! ! Boil the mixture for 2 hours. The solvent was then evaporated to dryness. The resulting orange oil is redissolved in 100 mA of 2N hydrochloric acid.

The acidic solution is boiled for 15 minutes and then left at ambient temperature for 18 hours. Then the solution is extracted with ether to extract benzaldehyde. Separate the aqueous phase and It is made alkaline by adding a powder.

Then extract with ethyl acetate. The organic phase is washed with water, dried and evaporated to dryness. . 4.75 g of the oily residue are triturated in a little ether and crystallized.

The triazole derivative is then reconsolidated with a minimal amount of acetonyl. thus , 1.4 g of product were obtained as crystals, melting point 96°.

This product has a melting point of 114-11 obtained by direct reaction with methylhydrazine. Shows the same IR spectrum as the 5° isomer. Similarly, chloroform-isopropylene The Rf by thin layer chromatography on the Ruamine 9:1 system was also the same.

The difference in melting point is that a product with a melting point of 96° has one molecule of water of crystallization according to microanalysis. This can be explained by showing the fact that

The compound with a melting point of 162° is clearly (2-amino-3-methyl-3-) 1.1 a Solilu 5)-amine derivative.

Mi7? )-piperidine 18.7 g of 4-acederaminobi-veridine, 3-(2-bromoethyl)-i 29.5 g of ndole and 13.0 g previously dissolved in 70 ml of dimethylformamide. A mixture of 3 g of triethylamine is stirred at ambient temperature for 20 hours. Concentrate this Dry to dryness, dissolve the residue in a small amount of water containing a few mj2 of ammonia, and then remove the aqueous layer. Extract with chloroform.

The chloroform solution is washed with water, dried, and then concentrated.

In this way, 30 g of the desired product was obtained as colorless crystals with a melting point of 160°.

Purification by recrystallization from acetonyl I-IJ gave a product with a melting point of 165°.

1-(indol-3-yl-methyl)-4-acetylaminopipe obtained in step A Dissolve 26g of lysine in 260mA of 2N hydrochloric acid, gradually raise the temperature and boil for 2.5 hours. Continue.

After cooling, the solvent is filtered and the filtrate is made alkaline by adding concentrated caustic soda. A spherical precipitate is obtained which crystallizes immediately.

Separate the dry crystals, wash with water and dry. As a result, a crystal with a melting point of 105-110° was found. 23 g of aminopiperidine was obtained as brown crystals.

According to thin layer chromatography, the product is homogeneous (single spot Rf = 0.4 5). Chromatography uses methanol-ion as the eluent. A sopropylamine 9:1 system was used. This compound can be used directly in the next synthesis step. Pure enough for use.

(N-cyano-8-methylisothioureido) 13.25 g of N-cyano-dime 300m with Chiruisothio Katana Rubo Fuichito! ! 24 g of 1 in a mixture with ethanol - (ground in ethyl). The crystals thus obtained are filtered off, dried and washed. ,dry. As a result, 27 g of isothioureide was obtained (m, p, -44°) .

Step D 1-(indol-3-yl-ethyl)-4-100 mff of ethanol 6.8 g of 1-(indol-3-yl-methyl)-4-(N-cyano-8 -methyl-isothioureido)-piperidine and 4.5 mA of hydrated hydrazine dissolve. The mixture is refluxed for 20 hours and the solution is evaporated to dryness. get orange oil When this is made into an acetonitrile solution, it crystallizes after several hours.

Separate the crystals, wash, rinse with ether and dry.

5.6 g of the given triazole are thus obtained. This is recycled from ethanol. and purify it. Melting point 200°. This product is crystalline with 1/2 molecule of water of crystallization. It is.

Example 221-(indol-3-yl-ethyl)-4-[(2-a,mino-3 -)riazolyl-5-amine)-methyl]-biveridine Step A 1-(indol-3-yl-ethyl)-4-piperidinocarboxami de 22.4 g of 3-(bromo-2- ethyl)-indole, 12.8 g of 4-piperidinocarboxamide and 10. Suspend 1 g of triethylamine.

After stirring for 18 hours, the mixture was concentrated to dryness and the oily residue was condensed in ammonia-containing water. Grind until crystallized. After leaving it in water overnight, filter out the crystals and strain with water. Wash with sun and dry. Colorless crystals with a melting point of 184° after recrystallization from ethanol As a result, 19 g of indolyl ethyl piperidine lupoxamide was obtained.

Thin layer chromatography using methanol-isopropylamine 9:1 system as eluent According to Raffy, the product is homogeneous (single spot with Rf=0.70).

Step B 1-(indol-3-yl-ethyl)-4-aminomethylpiperidine Lithium and aluminum hydrogen to L50rr+42 Tetrahy-I Lofran Suspend aluminum chloride LQg and add it while stirring to prevent the temperature from rising. , 20 g of 1-(indol-3-yl-ethyl)-4-piperidinocarboxa Add mido. After the addition is complete, the mixture is boiled for 4 hours.

Excess reactants are removed in small amounts with sufficient cooling so that the medium temperature does not rise above 0°. Decompose by adding water.

After filtration over a clay sold under the name CELIT, the solution is evaporated to dryness. Ru. Collect the oily residue, redissolve it in a small amount of ethanol, filter and reconcentrate Dry.

The liquid product thus crystallized stepwise, yielding 19 g of mono-gamma-minomethylpiperi. Got gin.

The product has two melting points, once melting at 80°, then solidifying and again at 13 ( Melts at 1-132°.

-Aminomethylpiperidine, 10.7 g methylN-animinodithiopower Heat the mixture of sulfonate and 300 mff of ethanol to boil for 4 hours .

This was cooled, then concentrated to dryness, and the isolated oil product was mixed with a small amount of ether. Add until crystals form.

The crystals are allowed to stand (1), filtered, dried, washed with ether, and dried (3), thus: 18 g of perinne was obtained as colorless crystals with a melting point of 150°.

], 00mjl! of 1-(indol-3-yl-ethyl) in ethanol. methyl)-4-(N-noanoS-methylisothioureidomethyl)-piperidine and a solution containing 4 mA of hydrated hydrazine is boiled for 18 hours.

After concentration to dryness, the residue is redissolved in acetonate (IJ) and the product is crystallized. . The uG solution was left for several hours, filtered, and the crystals were washed with γ-cetonyl-IJ and dried under reduced pressure. dry In this way, 6.3 g of the desired triazole was obtained. This has a melting point of 172 It is a colorless crystal.

Example 23 The following compounds were prepared according to the procedure of Example 1 or Example 14.

[minomethyl]-piperidine.

Tablet containing 2.5mg of the main ingredient.

1-[4-(p-fluorophenyl)-4-oxo-1-butyl]-4-(2 -amino-1,3,4-oxadiazolyl-5-methylamine)-piperidine 25g wheat starch 250g Lactose 175g Microcrystalline cellulose 45g Dicalcium phosphate 900g Macunium stearate 25g Carboquine methyl starch 17.5g 10.000 finished tablets with an average weight of 0.185 g.

Example 25 Tablet containing 5 main ingredients.

1-(penlanoxan-2-yl-methyl)-4-(2-amino-1,3,4 -) riazolyl-5-methylamino)-piperidi7 50g Wheat starch 400g Corn starch 220g Microcrystalline cellulose 375g Calcium sulfate 510g Carboxymethylcellulose 20g Ethyl cellulose 15g 10,000 finished tablets with an average weight of 0.150 g.

The average lethal dose (LDs.) for 10 CESAL-reared EOPS female 20-day-old rats. O, E, J, C aITlpbell & IIl, Richter et al.'s method (Acta, Ph arm, & Toxicol, 25 (1967>345>). Established. These test animals were continuously observed for 5 days. The number of deaths was counted. the As a result, depending on the type of compound, the average lethal dose is 360mg/kg-1200m It was within the range of g/kg.

b) Determination of antihypertensive effect Tests were conducted on each lot of male rats whose abdominal aorta was previously ligated to create a hypertensive state. I did it.

Compounds of the invention were administered orally at doses of 1.2 mg/kg and 5 mg/kg. did. This resulted in a pronounced and sustained reduction in blood pressure.

Additionally, the compounds of the invention may be administered to anesthetized normotensive or normotensive rats. For the most active compound, administer 2 to 50 μg/’g to anesthetized dogs with and for other compounds at varying doses of 20-50 μg/kg. When administered internally, the compound of the present invention causes a state of extremely pronounced hypotension and has a peripheral vasodilator effect. It does not cause any use. Over the dose range, vasodilation also increased skin temperature in the rat hind paw. was also not confirmed.

international search report

Claims (1)

[Claims] (1,i 2-amino-5-[(araruazole) of the following general formula (I). J-Top, A" is a monochrome 1' near or pink aryl group or a heterocyclic aryl group. There is a lyl group, and X is -(Cl12)n'-;-Cll011-(C1l□ ) n, -: -[0-([:R2) n, - and C7, [1 is 1. 2.3 or 4, nl is 1.2 or 3, n゛ is O1■ or 2, are the same group, - is a lower alkyl group or a lower alkyl group, an optionally substituted alkylene nail selected from t, (ruo) ¥3 , 11(・t(Formula (A). where R3 is hydrogen, a lower alkyl group, an aryl group, a lower aralkyl group, and an aminotriazole having formula (B). Here, Z is -1141-1-NR3-1, but R3 is as defined above, or or oxygen, It is a heterocyclic group selected from the group consisting of 1,4 cyasole represented by (2) Addition salts of the compound according to claim 1 with an inorganic acid or an organic acid. (3) An optically active form of the compound according to claim 1 or 2. (4) Any one of the manual claims represented by the following general formula (I△) Compound. n and n' are as defined above, and Z is NH, NR, or or oxygen, where R3 is as defined above. (5) Any one of claims 1 to 4 represented by the following general formula (IB) Compounds mentioned: Here, the substituents R, R3 and K'' and p1n+ and n' are as defined above. be. (6) The compound according to any one of claims 1 to 4, represented by the general formula (rc) Compound: Q Here, the substituents R, K' and p, n, , n' are as defined above. (7) The compound according to any one of claims 1 to 4 represented by general formula (ID) Compound: Here, the substituents R, R, and ' and p, rl+ and n' are as defined above. It is. (8) The compound according to any one of claims 1 to 4 represented by general formula (IE) Compound: Here, R, ni', p, Z, and nl and n' are as defined above. (9) 1-[(4-p-fluorophenyl)-4-oxobutyl-L:]- 4-[(2-amino-1,3,4-)lyazole-5-amino-methyl]-piperi The compound according to claim 1 or 2 known as gin and its hydrochloride Compound. 00 A small amount of the compound according to any one of claims 1 to 9 as the main component at least one inert, non-toxic and pharmaceutically acceptable auxiliary agent or vehicle. A pharmaceutical composition characterized in that it is contained in a blended or mixed form. (11) The form is suitable for parenteral, oral, rectal, sublingual or subcutaneous administration. 11. The pharmaceutical composition according to claim 10, characterized in that: (12) The amount of the main component is 01 to 50 mg per unit dose. The pharmaceutical composition according to claim 10 or 11. (13) General formula (■). Here, Ar, X# and n' are as defined above, and Z. is oxygen or sulfur, and R4 is a lower alkyl group, N-cyano-isothiourea or isourea represented by the general formula (■): NZ-NH3(I) However, Z is as defined above, When 2 is oxygen, by reacting with the amine derivative represented by the general formula (I ”): 2-amino-3-oxa-1,4-diazole with When it is a mino group, 2-amino-13,4-tria represented by formula (I''): or when Z is NR3, it is represented by the formula and can be separated by physical means. Substituted 2-amino-1°: 3.4-1-! Forming an asol mixture A method for producing a compound according to any one of claims 1 to 9, characterized in that Law. (14) Supplementary salt 1f co-composition by adding inorganic acids or 11-organic acids to the river. 14. The method according to claim 13, characterized in that the culm contains 4 T culms. (15) Furthermore, 9′)′f! - including supplementary steps of salt formation and resolution with active acids (hyperoxidase); 12. The method according to claim 13 or 11, characterized in that: